HEPATOBLASTOMA AND HEPATOCELLULAR
CARCINOMA IN CHILDHOOD AND ADOLESCENCE :WHAT NEWS ?
B. BRICHARD, MD,
PhD, Department of Paediatric Haematology and Oncology, Cliniques Universitaires
Saint Luc, University of Louvain, Brussels, Belgium.
Primary liver tumours in children account for approximately 5% of childhood neoplasms and over two-thirds occur within the first year of life. The biology and behaviour of hepatoblastoma (HBL) and hepatocellular carcinoma (HCC) differ but therapeutic strategy is similar for both tumours. If survival rate in HBL currently exceeds 70%, prognosis of HCC remains poor with less than 25% survival.
A number of biological clues have recently emerged regarding the characteristics of hepatoblastoma, with the demonstration of loss of heterozygosity on chromosome 11p15 in a number of tumours and also the association between hepatoblastoma and familial polyposis coli. The FAP gene has been located in chromosome 5q. These observations are a further justification for initial biopsy to obtain suitable tissue for studying the molecular basis of this tumour.
In over 80% of HBL and in over 60% of HCC raised levels of alpha-fetoprotein (AFP) are detected. This is useful both for diagnosis and response assessment. Rate of AFP decline correlates with outcome. It could be argued that with the presence of a liver mass and raised AFP no further investigations are required, as the chemotherapy is the same for HBL and HCC but this approach will lead to misdiagnosis of rare intrahepatic tumour as teratoma. Second, as a significant percentage of masses following chemotherapy are found to be entirely necrotic, a firm diagnosis may not be achieved at the time of post-chemotherapy resection. There is now a general consensus that provided there is no significant risk associated with biopsy this should be done except in the case of a very unwell infant.
Hepatoblastoma can be classified into a range of subgroups, although the prognostic significance of these are unclear : 75% are epithelial (fetal and embryonal types) and the remainder are mixed epithelial or mesenchymal (figure 1). At the present time, no stratification is made on the basis of pathology ; however, patients with pure fetal histology, particulary those with small localised tumours may have a better outcome.
The fibrolamellar variant of hepatocellular carcinoma is associated with a lower degree of chemosensibility (figure 2). If complete resection is achieved, it has a favourable outlook but in the presence of non-localised and unresecable disease the disease outcome is particulary poor.
Hepatic tumours are generally divided into localised and metastatic disease. The majority of distant metastases are in the lung, although bone may be involved. Of more important is the staging of the primary tumour. Even with effective primary chemotherapy, surgery has a vital role to play in achieving cure. Outcome is poor if complete resection is not achieved. The actual International Society of Paediatric Oncology (SIOP) pre-treatment grouping system is shown in figure 3.
Is surgey alone ever adequate for HBL and HCC ?
This is unlikely, but how minimal chemotherapy can be remains to be defined. The current SIOP study is evaluating the role of a single-agent cisplatin in both resected and small volume primary disease. Because of the efficacy of primary chemotherapy in HBL, primary resection is generally restricted to small group I tumours.
What chemotherapy should be used ?
The relative simple PLADO (Cisplatin/doxorubicin) regimen appears to be effective as any other combination regimen (figure 4). Although there was initial concern about late effects with regard to cardiac toxicity and impaired renal function, the introduction of a continous infusion regimen for both cisplatin and doxorubicin has significantly reduced these toxicities. More complex regimens appear to add little compared with the PLADO regimen.
Figure 4 : Hepatoblastoma. (a) CT scan at diagnosis before 4 courses of PLADO (Cisplatin/doxorubicin) chemotherapy ; (b) CT scan after chemotherapy.
When should liver transplantation be considered ?
Liver transplantation is usually limited to children with unresecable but chemosensitive primary tumours, either HBL or HCC, where more than one lobe is involved. Transplantation may be the only way of achieving complete remission.
The issue of children in children with lung metastases is less clear. For HBL, where the cure rate now exceeds 70% for such patients, provided the tumour is chemosensitive but the primary remains unresecable there is justification for transplantation.
Is there a role for surgery to lung metastases ?
HBL is one of the tumours in which lung metastases may be genuinely localised and, therefore, surgical exploration of postchemotherapy residual imageable lesions is justified.
What is the role of local radiotherapy ?
Lung irradiation is not necessary in chemosensitive lung metastases in HBL.
Beneficial effect of local irradiation to sites of microscopic residual disease following incomplete postchemotherapy resection remains controversial, but in the absence of any other option and the knowledge that microscopic disease at this stage invariably progresses, there is an argument for its use.
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